Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.

The adverse reactions that result from KEPPRA injection
use include all of those reported for KEPPRA tablets and oral solution.
Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam
result in equivalent Cmax, Cmin, and total systemic exposure to levetiracetam
when the IV levetiracetam is administered as a 15-minute infusion.

Partial Onset Seizures

Adults

In controlled clinical studies using KEPPRA tablets in
adults with partial onset seizures, the most common adverse reactions in adult
patients receiving KEPPRA in combination with other AEDs, for events with rates
greater than placebo, were somnolence, asthenia, infection, and dizziness. Of
the most common adverse reactions in adults experiencing partial onset seizures,
asthenia, somnolence, and dizziness occurred predominantly during the first 4
weeks of treatment with KEPPRA.

Table 4 lists adverse reactions that occurred in at least
1% of adult epilepsy patients treated with KEPPRA tablets participating in
placebo-controlled studies and were numerically more common than in patients
treated with placebo. In these studies, either KEPPRA or placebo was added to concurrent
AED therapy.

* Adverse reactions occurred in
at least 1% of KEPPRA-treated patients and occurred more frequently than
placebo-treated patients

In controlled adult clinical
studies using KEPPRA tablets, 15% of patients receiving KEPPRA and 12%
receiving placebo either discontinued or had a dose reduction as a result of an
adverse reaction. Table 5 lists the most common ( > 1%) adverse reactions that
resulted in discontinuation or dose reduction and that occurred more frequently
in KEPPRA-treated patients than in placebo-treated patients.

Pediatric Patients 4 Years to
< 16 Years

The adverse reaction data
presented below was obtained from a pooled analysis of two controlled pediatric
clinical studies using an oral formulation in pediatric patients 4 to 16 years
of age with partial onset seizures. The most common adverse reactions in
pediatric patients receiving KEPPRA in combination with other AEDs, for events
with rates greater than placebo, were fatigue, aggression, nasal congestion,
decreased appetite, and irritability.

Table 6 lists adverse reactions
from the pooled pediatric controlled studies (4 to 16 years of age) that
occurred in at least 2% of pediatric KEPPRA-treated patients and were
numerically more common than in pediatric patients treated with placebo. In
these studies, either KEPPRA or placebo was added to concurrent AED therapy.

* Adverse reactions occurred in
at least 2% of pediatric KEPPRA-treated patients and occurred more frequently
than placebo-treated patients

In the controlled pooled
pediatric clinical studies in patients 4-16 years of age, 7% of patients
receiving KEPPRA and 9% receiving placebo discontinued as a result of an
adverse reaction.

Pediatric Patients 1 Month to
< 4 Years

In the 7-day controlled
pediatric clinical study using an oral formulation of KEPPRA in children 1
month to less than 4 years of age with partial onset seizures, the most common
adverse reactions in patients receiving KEPPRA in combination with other AEDs,
for events with rates greater than placebo, were somnolence and irritability.
Because of the shorter exposure period, incidences of adverse reactions are
expected to be lower than in other pediatric studies in older patients.
Therefore, other controlled pediatric data, presented above, should also be
considered to apply to this age group.

Table 7 lists adverse reactions that occurred in at least
5% of pediatric epilepsy patients (ages 1 month to < 4 years) treated with
KEPPRA participating in the placebo-controlled study and were numerically more
common than in patients treated with placebo. In this study, either KEPPRA or
placebo was added to concurrent AED therapy.

* Adverse reactions occurred in
at least 5% of KEPPRA-treated patients and occurred more frequently than
placebo-treated patients

In the 7-day controlled
pediatric clinical study in patients 1 month to < 4 years of age, 3% of
patients receiving KEPPRA and 2% receiving placebo either discontinued or had a
dose reduction as a result of an adverse reaction. There was no adverse
reaction that resulted in discontinuation for more than one patient.

Myoclonic Seizures

Although the pattern of adverse
reactions in this study seems somewhat different from that seen in patients
with partial seizures, this is likely due to the much smaller number of
patients in this study compared to partial seizure studies. The adverse
reaction pattern for patients with JME is expected to be essentially the same
as for patients with partial seizures.

In the controlled clinical
study using KEPPRA tablets in patients with myoclonic seizures, the most common
adverse reactions in patients receiving KEPPRA in combination with other AEDs,
for events with rates greater than placebo, were somnolence, neck pain, and
pharyngitis.

Table 8 lists adverse reactions
that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing
myoclonic seizures treated with KEPPRA tablets and were numerically more common
than in patients treated with placebo. In this study, either KEPPRA or placebo
was added to concurrent AED therapy.

Table 8: Adverse Reactions*
in Patients 12 Years Of Age and Older With Myoclonic Seizures

KEPPRA
(N=60) %

Placebo
(N=60) %

Somnolence

12

2

Neck pain

8

2

Pharyngitis

7

0

Depression

5

2

Influenza

5

2

Vertigo

5

3

* Adverse reactions occurred in
at least 5% of KEPPRA-treated patients and occurred more frequently than
placebo-treated patients

In the placebo-controlled study
using KEPPRA tablets in patients with JME, 8% of patients receiving KEPPRA and
2% receiving placebo either discontinued or had a dose reduction as a result of
an adverse reaction. The adverse reactions that led to discontinuation or dose
reduction and that occurred more frequently in KEPPRA-treated patients than in
placebo-treated patients are presented in Table 9.

Primary Generalized
Tonic-Clonic Seizures

Although the pattern of adverse
reactions in this study seems somewhat different from that seen in patients
with partial seizures, this is likely due to the much smaller number of
patients in this study compared to partial seizure studies. The adverse
reaction pattern for patients with primary generalized tonic-clonic (PGTC)
seizures is expected to be essentially the same as for patients with partial
seizures.

In the controlled clinical
study that included patients 4 years of age and older with PGTC seizures, the
most common adverse reaction in patients receiving KEPPRA oral formulation in
combination with other AEDs, for events with rates greater than placebo was
nasopharyngitis.

Table 10 lists adverse
reactions that occurred in at least 5% of idiopathic generalized epilepsy
patients experiencing PGTC seizures treated with KEPPRA and were numerically
more common than in patients treated with placebo. In this study, either KEPPRA
or placebo was added to concurrent AED therapy.

Table 10: Adverse Reactions*
in Patients 4 Years of Age and Older With PGTC Seizures

KEPPRA
(N=79) %

Placebo
(N=84) %

Nasopharyngitis

14

5

Fatigue

10

8

Diarrhea

8

7

Irritability

6

2

Mood swings

5

1

* Adverse reactions occurred in
at least 5% of KEPPRA-treated patients and occurred more frequently than
placebo-treated patients

In the placebo-controlled
study, 5% of patients receiving KEPPRA and 8% receiving placebo either
discontinued or had a dose reduction during the treatment period as a result of
an adverse reaction.

This study was too small to
adequately characterize the adverse reactions that could be expected to result
in discontinuation of treatment in this population. It is expected that the
adverse reactions that would lead to discontinuation in this population would
be similar to those resulting in discontinuation in other epilepsy trials (see
tables 5 and 9).

In addition, the following
adverse reactions were seen in other controlled adult studies of KEPPRA:
balance disorder, disturbance in attention, eczema, memory impairment, myalgia,
and vision blurred.

Comparison of Gender, Age and
Race

The overall adverse reaction
profile of KEPPRA was similar between females and males. There are insufficient
data to support a statement regarding the distribution of adverse experience
reports by age and race.

Postmarketing Experience

The following adverse reactions
have been identified during postapproval use of KEPPRA. Because these reactions
are reported voluntarily from a population of uncertain size, it is not always
possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.